CD9-mediated activation of the p46 Shc isoform leads to apoptosis in cancer cells
CD9-mediated activation of the p46 Shc isoform leads to apoptosis in cancer cells
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DOI：
10.1242/jcs.01201
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发表时间：
2004-07-01
影响因子：
4
通讯作者：
Shinomura, Y
中科院分区：
文献类型：
--
作者：
Murayama, Y;Miyagawa, JI;Shinomura, Y
CD 9是四跨膜蛋白家族的成员，已被证明参与一系列细胞活动，包括迁移、增殖和粘附，但其介导这些事件的分子机制尚不清楚。在这里，我们发现，抗CD 9单克隆抗体ALB 6抑制细胞增殖，降低细胞活力，诱导不仅是细胞凋亡的形态学变化，但也分子的变化，证明了TUNEL和annexin-V染色。对于ALB 6诱导细胞凋亡的可能机制，ALB 6在5-15分钟内激活c-Jun氨基末端激酶/应激激活蛋白激酶（JNK/SAPK）和p38丝裂原激活蛋白激酶（MAPK），以及在24-48小时内激活caspase-3。值得注意的是，ALB 6特异性地诱导p46 Shc亚型的酪氨酸磷酸化，并且其显性负性形式的过表达完全抑制了ALB 6诱导的JNK/SAPK、p38 MAPK和caspase-3的活化，从而抑制了凋亡性细胞死亡。这些结果表明，在人类肿瘤细胞系中，CD 9可能通过特异性信号调节凋亡。
CD9, a member of the tetraspanin family, has been shown to be involved in a range of cellular activities, including migration, proliferation and adhesion, but the molecular mechanisms by which it mediates such events is unclear. Here, we found that anti-CD9 monoclonal antibody ALB6 inhibited cell proliferation, reduced cell viability and induced not only morphological changes specific to apoptosis but also molecular changes, as evidenced by TUNEL and annexin-V staining. For the possible mechanism of ALB6-induced apoptosis, ALB6 activated the c-Jun NH2-terminal kinase/stress-activated protein kinase (JNK/SAPK) and p38 mitogen-activated-protein kinase (MAPK) within 5-15 minutes, as well as caspase-3 within 24-48 hours. It is noteworthy that ALB6 induced tyrosine phosphorylation of the p46 Shc isoform specifically and that the overexpression of its dominant-negative form completely suppressed the ALB6-induced activation of JNK/SAPK, p38 MAPK and caspase-3, resulting in the inhibition of apoptotic cell death. These results suggest that CD9 might regulate apoptosis through the specialized signals in human cancer cell lines.